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Probiotics
*Research Scientist, Strategic-Discovery Research and Development, Ross Products Division, Abbott Laboratories, Columbus,
OH.
Address reprint requests to JoMay Chow, PhD, Strategic-Discovery Research and Development, Ross Products Division, Abbott
Laboratories 105670/RP3-2, 625 Cleveland Ave, Columbus,
OH 43215-1724.
2002 by the National Kidney Foundation, Inc.
1051-2276/02/1202-0001$35.00/0
doi:10.1053/jren.2002.31759
76
History
The group of microorganisms most frequently
regarded as probiotics, the lactic acid bacteria, has
a long history of consumption by humans. These
bacteria, which originally served to prevent spoilage of food by undesirable organisms, were con-
77
Safety
Overall, traditional dairy strains of probiotic
bacteria, particularly those belonging to the Lactobacillus and Bidobacterium genera, are considered to be of low pathogenic potential when
given to healthy humans.23,24 Even after many
years of use, probiotics have been linked to only
1 clinical infection.25 In this case, a purulent
viscous uid specimen was aspirated from a hepatic abscess in a 74-year-old woman with a
history of hypertension, noninsulin-dependent
diabetes mellitus, mild abdominal discomfort, and
mild fever. The aspirate contained virtually a pure
culture of gram-positive coccobacilli. Results
from enzymatic testing and molecular analysis
(polymerase chain reaction assay and pulsed-eld
gel electrophoresis) of the culture aspirate were
indistinguishable from those of Lactobacillus strain
GG. An interview with the patient revealed that
she had been ingesting approximately 0.5 L Lac-
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JOMAY CHOW
79
Mechanisms of Action
The mechanisms by which probiotics exert
biological effects are still poorly understood, but
the nonspecic terms colonization resistance or
competitive exclusion are often used to explain
their mode of action. Colonization resistance or
competitive exclusion describes a phenomenon
whereby the indigenous anaerobic ora limits
the concentration of potentially pathogenic
(mostly aerobic) ora in the digestive tract.51
The concept of competitive exclusion was rst
developed during the early 1970s when it was
discovered that the administration of mixed adult
intestinal microorganisms conferred adult-type
resistance against salmonella infection to newly
hatched chicks.52 Even more striking evidence of
the protective effect of the normal intestinal microbiota comes from studies of Clostridium difcile
pseudomembranous enterocolitis in both animal
models53 and in patients who experience multiple
recurrences of diarrhea or colitis after discontinuation of successful antibiotic therapy.54-58
Some of the specic mechanisms by which the
intestinal microbiota exclude undesirable organisms are thought to include the following:59,60 (1)
production of inhibitory substances, (2) blocking
of adhesion sites, (3) competition for nutrients,
(4) degradation of toxin receptor, and (6) stimulation of immunity. Although probiotic bacteria
are thought to mediate their effects by using some
of the same mechanisms as the native intestinal
ora, probiotics may also work through other
modes of action such as supplying enzymes or
inuencing enzyme activity in the gastrointestinal
tract.59 In fact, some studies have even suggested
that probiotics, killed cells, or certain cell fractions exert antimutagenic61 or adjuvant effects,62
inuence cytokine expression,63 or inuence the
development of allergies.64
Reference
Antibiotic-associated diarrhea
Candida vaginitis
Clostridium difcile
Cryptosporidiosis
Helicobacter pylori gastroenteritis
Hepatic encephalopathy
Inammatory bowel disease
Lactose intolerance
Necrotizing enterocolitis
Rotavirus diarrhea
Small bowel bacterial overgrowth
in uremia
Suppression of chemically induced
large bowel tumors
Urinary tract infections
65
66
67-69
70
71
72
73
120
74,75
121-123
46,47,76
78
79,80
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JOMAY CHOW
Commercial Products
Many culture-containing dairy products such
as yogurts and culture-added milks contain live
microorganisms, but these products require refrigeration and have relatively short shelf lives that
are measured in terms of weeks instead of
months. On the other hand, freeze-dried microorganisms can remain viable indenitely under
ideal storage conditions. Therefore, because it has
been assumed that viability is required for biologic activity, probiotic product forms have been
largely limited to capsules, tablets, and powders.
Even so, some commercial products, including
those in tablet and capsule forms, display a
marked discrepancy between the claimed and
actual count of viable bacteria and/or a discrepancy between the species shown on the label and
the actual species present in the product.81
A number of probiotic products are available in
the United States. As an example, Lactinex (Becton-Dickinson; Franklin Lakes, NJ), a powdered
or tabletted product consisting of a mixture of L
acidophilus and Lactobacillus bulgaricus, has been on
the market since the early 1960s. However, clinical studies suggest that this preparation was ineffective for preventing or altering the course
of enterotoxigenic Escherichia coli diarrhea in
adults82,83 and for reducing the incidence or
duration of travelers diarrhea.84 In addition, a
number of new probiotic-containing products
such as Culturelle (L GG capsules; CAG Functional Foods, Omaha, NE) and Probiotica (Lactobacillus reuteri tablets; McNeil Consumer
Healthcare, Ft Washington, PA) have been
launched during recent years. Some of these organisms have undergone extensive clinical testing.
gredient that benecially affects the host by selectively stimulating the growth and/or activity
of one or a limited number of bacteria in the
colon, and thus improves host health. At the
present time, a large number of ingredients are
known to escape hydrolysis in the small intestine,
but only 4 ingredients also meet the criteria set
forth for prebiotics in stimulating the growth of
certain bacteria: transgalactosylated disaccharides,
xylooligosaccharides, soybean oligosaccharides
and fructooligosaccharides (FOSs). This review
focuses solely on FOS because it was the rst
prebiotic oligosaccharide made available in the
United States and because much more is known
about it than other prebiotics.
Structure of FOSs
FOSs are short- and medium-length chains of
-D-fructans in which fructosyl units are bound
by 2-1 glycosidic linkages (Fig 1). Some molecules also contain glucose as the rst moiety.
These compounds occur naturally in many
foods85 including wheat, onions, bananas, honey,
garlic, and leeks, but more puried forms may
be purchased commercially. Long-chain fructan polymers, referred to as inulin (Raftiline
[DRAFTI Active Food Ingredients, Tienen, Belgium] or Frutat [Imperial-Suiker Unie, Sugar
Land, TX]), are isolated from chicory root. These
fructans can be partially hydrolyzed by enzymes
to make a type of FOS known as oligofructose
(Raftilose [DRAFTI Active Food Ingredients]).
FOSs can also be synthesized from sucrose by
using enzymes from Aspergillus niger to make
Neosugar (Actilight [Beghin-Meiji Industries,
Paris, France], Meioligo [Meiji Seika Kaisha, Tokyo, Japan], NutraFlora [GTC Nutrition, Westminster, CO]).
Prebiotics
Denition
The term prebiotic, rst coined by Gibson and
Roberfroid,5 refers to a nondigestible food in-
Safety of FOSs
The US Food and Drug Administration has
not yet approved FOS as generally recognized as
safe (GRAS), but existing evidence suggests that
the government will eventually grant this ingredient GRAS status.86 As mentioned previously,
FOSs occur naturally in a wide variety of foods.
In fact, Americans consume approximately 2.5 g
of inulin and oligofructose daily (range of 1 to
4 g), mostly from wheat and onions.87 In addition, several US companies have already selfafrmed either oligofructose or Neosugar FOS as
GRAS by having an expert panel review documentation regarding the safety of this ingredient.
On a worldwide basis, NutraFlora FOS has been
incorporated into at least 500 food products. In
Japan, FOSs have been approved by the Minister
of Health and Welfare as foods for specied
health use (FOSHU) and have been included in
at least 13 products that function as table sugar.
In terms of safety, the ingestion of FOSs cause
few adverse effects, and the adverse effects are
minor in nature.88 Because FOSs possess many of
the same physiologic properties as dietary ber,
the consumption of FOSs can lead to symptoms
just like those encountered after a sudden increase
in dietary ber intake with the severity of symptoms related to intake level.88 Common symptoms include atulence, cramping, and diarrhea,
but effects are only temporary.
The safety and tolerance of FOSs were actually
measured in stable hemodialysis patients.89 Seventy-nine normally nourished, stable, anuric, adequately dialyzed, adult outpatients with endstage renal disease were randomized to 1 of 3
treatment groups in a prospective, controlled,
single-blind, parallel study. The treatment groups
included a standard medical nutritional and 2
renal nutritionals with one of the renal nutritionals containing added -carotene and FOSs. During the 3-week long study, gastrointestinal symptoms and bowel habits were recorded during a
1-week baseline period and during 2 weeks of
treatment. Subjects who were randomized to the
FOS-containing treatment ingested an average of
15.6 0.9 to 18.5 1.2 g FOSs daily, and those
in the other 2 groups did not ingest any FOSs.
Results from the study showed that the number
of instances in which gastrointestinal symptoms
required treatment was not different between the
renal nutritional without FOSs and the renal
81
Figure 2. Fermentation of carbohydrates by colonic bacteria. Fermentation results in the production of SCFAs, bacteria cell growth, gas, and heat.
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JOMAY CHOW
Conclusions
Probiotics and FOSs could potentially provide
several benets to renal patients. As an example,
probiotics may reduce the levels of certain toxic
compounds generated by the small bowel ora
that are thought to contribute to some of the
neurologic symptoms of uremia. On the other
hand, FOSs, which also happen to have a very
low glycemic index and lower energy content
than glucose or fructose, could potentially function in the capacity of a dietary ber supplement
to help maintain regularity in this patient population or as a reduced calorie sweetener for diabetic patients.
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